17-(aliphatic hydrocarbonoxy) and 17-(substituted aliphatic hydrocarbonoxy) estrane derivatives



United States Patent Office 3,374,251 Patented Mar. 19, 1968 This invention relates to novel cyclopentanopolyhydrophenanthrene derivatives and to processes for their preparation.

More particularly, this invention relates to novel 17- (aliphatic hydrocarbonoxy) and 17-(substituted aliphatic hydrocarbonoxy)estrane derivatives represented by the general formulas: I

O-R-RO In these formulas, R represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon residue containing from 1 to carbon atoms, inclusive, such as ethylene, ,i.e., -CI-I CH propylene, ,butylene, hexamethylene, octamethylene, isooctalene, 2,3-dimethylheptalene, 2-methyl-3-ethylheptalene, but-l-enylene, Z-methylbut-2-enylene, but-l-inylene, isooct-Z-enylene, 2,3-dimethylhept-Z-enylene, 2-methyl-3-ethylhept 2 enylene, and the like, With R preferably being ethylene in Formula B; the group OR .represents a hydroxyl group, an acyloxy group or an ether group; i.e., R represents hydrogen, an acyl group, or a saturated or unsaturated, straight or branched chain aliphatic, cycloaliphatic or aromatic-aliphatic group containing from 1 to 12 carbon atoms, inclusive, and preferably a hydrocarbon group containing up to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, isoamyl, n-decyl, cyclohexyl, cyclohexenyl, benzyl, and the like, and R represents hydrogen or methyl.

In the grouping 0R which is substituted on a primary, secondary or tertiary carbon atom-of the group R, R represents hydrogen or an acyl group.

The symbol X represents hydrogen, a halogen, e.g., fiuorineor chlorine, an N,N-dialkylamino group, preferably an N,N-di(lower) alkylamino group such as N,N-dimethylamino and the like, a carboxyl group, a cyano group, or an aldehydic oxygen (i.e., an oxygen atom doubly bonded to a carbon atom of the group R, said carbon atom also having a hydrogen atom attached thereto). a

The symbol Z represents a saturated linkage or a double bond at the 6, 7-position in the steroid nucleus.

This invention further relates to the novel 17-(aliphatic hydrocarbonoxy)- and 17-(substituted aliphatic hydrocarbonoxy)-A -estren-3-ones obtained from said 17-(aliphatic hydrocarbonoxy) and 17-(substituted aliphatic hydrocarbonoxy) estrane derivatives and represented by the general formulas:

O-R-O R In these formulas R and R have the same meaning as set forth hereinabove for Formulas A and B, with R preferably being ethylene in Formula D, and Y represents hydrogen, a halogen, e.g. fluorine or chlorine, or an N,N-dialkylamino group, preferably an N,N-di(lower) alkylamino group such as N,N-dirnethylamino and the like.

The symbol 5 at the 17-positionin the above formulas and in those that follow signifies that the aliphatic hydrocarbonoxy or substituted aliphatic hydrocarbonoxy substituent at the 17-position can be in either the ocor the flconfiguration.

The acyl and acyloxy groups referred to hereinabove are derived from carboxylic acids, preferably hydrocarbon carboxylicacids, of less than 12 carbon atoms. These acids can be' saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphaticv chain, or aromatic, and may be-substitutedwith functional groups such as hydroxyl groups, alkoxy groups containing up to 5 carbon atoms, acyloxy. groups containing up to 12 carbon atoms, nitro groups, aminov groups and halogens. Typical ester groups are the acetate, trimethylacetate, t-butylacetate, aminoacetate, phenoxyacetate, propionate, fichloropropionate, cyclopentylpropionate, enanthate and benzoate.

The novel 17-(aliphatic hydrocarbonoxy) and 17-(substituted aliphatic hydrocarbonoxyl)-A -estratrienes represented by Formula A above have remarkable estrogenic activity, and are useful in fertility control and in lowering chlosterol levels in blood. In addition, they serve as'intermediates for the preparation of thecompounds of Formulas B and C.

The novel 17-(aliphatic hy-drocarbonoxy) and 17-su stituted aliphatic hydrocarbonoxy)A estratrienes represented by Formula B above are also strong estrogenic agents with enhanced blood chlosterol-lowering activity. In addition, they serve as intermediates for the preparation of the compounds of FormulaD. Y

The novel 17,-(aliphatic hydrocarbonoxy)- and 17-(substituted aliphatic hydrocarbonoxy)-A -estren-3-ones repre sented by Formulas C and D above are anabolic-androgenic agents having a favorable anabolic-androgenic ratio. They alsohave'anti-estrogenic, anti-gonadotropic, antifibrillatory and appetite-stimulating properties, and further serve to lower blood chlosterol levels, relieve 'premenstrual tensionand suppress the output of the pituitary gland.

The compounds of the present invention can be obt'ained bythe methods illustrated by the following sequence of reactions:

/R\ c) o l R 0- R- o-n-x g-a-on In the above formulas each of R, R R R X, Y and Z have the same meanings as set forth hereinabove for Formulas A-D. f

In practicing the methods outlined above, the estrone derivative (I) employed as the starting material, e.g., estrone methyl ether, is reacted with a dihydric alcohol, preferably an aliphatic hydrocarbon diol, of up to 10 carbon atoms, such as ethylene glycol, propylene glycol-1,2, propylene glycol-1,3, butanediol-1,3, butanediol-1,4, hexane'diol-1,6, hexanediol-2,3, octamethylene glycol, and the like, to yield the corresponding 17-ketal (II), e.g., 17-(cycloethylenedioxy)-3-methoxy-A estratriene. This reaction will generally be carried out in the presence of a strong acid,-e.g., p-toluenesulfonic acid, preferably in solution in an inert organic solvent such as benzene and the like, at reflux temperature, and will usually take about 16 hours, although longer or shorter reaction times coupled with lower or higher temperatures may be employed if desired.

The 17-ketal (II) is then treated with a'cleaving agent, as described in my copending US. patent application Ser. No. 282,848, filed on May 24, 1963, now Patent No. 3,193,563, e.g.a double metal hydride containing at least one element of sub-group III-A of the Periodic Chart as set forth at pages 56 and 57 of Langes Handbook of Chemistry, Ninth edition (Sandusky, Ohio: Handbook Publishers, Inc., 1956), such as lithium aluminum hydride,

potassium aluminum hydride, magnesium aluminum hydride, lithium'gallium hydride, zinc aluminum hydride, sodium horohydride, potassium horohydride, aluminum borohydride, and the like, together with a Lewis acid containing no active hydrogen, and preferably a Lewis acid containing an element having an atomic number of 26 to 28 inclusive or an element of sub-group III-A' of the Periodic Chart, such as ferric chloride, boron trifluoride, boron trichloride, aluminum fluoride, aluminum chloride, aluminum bromide, gallium chloride, and the like, to yield the corresponding 17aand 17fi-(hydroxy aliphatic hydrocarbonoxy)-A -estratriene R and 17i3-(2'hydroxyetho'xy)-3-methoxy-A -estratriene being obtained by reacting l7-(cycloethylenedioxy)- 3-methoxy-A -estratriene with lithium aluminum hydride and aluminum chloride in tetrahydrofurane. This reaction will generally be carried out in an organic solvent having an ether function in its molecule, e.g., diethyl ether, tetrahydrofuran, and the like, at a temperature ranging from room temperature (about 25 C.) or lower to reflux temperature or above for a period of time ranging anywhere from about 30 minutes to about 24 hours. The 17 and l7 3-derivatives can be separated by conventional chromatographic methods.

These 17ocand 17p-(hydroxy aliphatic hydrocarbonoxy)-A -estratrienes, e.g., 170:- and 17B-(2-hydroxyethoxy)-3-methoxy-A -estratriene, when tosylated byv known procedures, e.g., using tosyl chloride in pyridine, yield the corresponding 17-(tosyloxy aliphatic hydrocarbonoxy)-A -estratrienes, e.g., 17ozand 17p- (2-tosyloxy ethoxy)-3-meth0xy-A -estratriene.

These tosylated intermediates, when treated at reflux temperature with an alkali metal halide, such as lithium chloride, potassium fluoride, potassium chloride, sodium chloride, and the like, preferably in an inert organic solvent such as dimethylformamide and the like, yield the corresponding 17-(halo aliphatic hydrocarbonoxy)- A -estratrienes (IV; X=halogen), e.g., 1711- and 17 8-(2'-fluoroethoxy-3-methoxy)-A -estratriene being obtained -by reacting l7aand 17B-(2'tosyloxyethoxy)- 3-methoxy-A -estratriene with potassium fluoride.

Similarly, treatment of the l7-(tosyloxy aliphatic hydrocarbonoxy)-estratriene intermediates with a dialkyl amine, preferably a di(lower) alkyl amine such as dimethyl amine, diethyl aminemethyl propyl amine, and the like, preferably in solution in an inert organic solvent such as dioxane and the like; gives the corresponding 17w and l7fi-(N,N-dialkylamino aliphatic hydrocarbonoxy)-A -estratrienes [IV; X=N(alkyl) e.g., 17aand 17B-[2'-(N,N-dimethylamino)-ethoxy] 3-methoxy- A -estratriene.

Treatment of the tosyloxy intermediates with an alkali metal cyanide, e.g. sodium cyanide, potassium cyanide, and the like, preferably in solution in an inert organic solvent such as acetonitrile and the like, produces the corresponding 17:1- and l7fi-(cyano aliphatic hydrocarbonoxy)-A -estratrienes (IV; X=CN), e.g., 17aand l7fl-(2'-cyanoethoxy)-3-methoxy-A -estratriene.

These -17-(cyano aliphatic hydrocarbonoxy) compounds, when subjected to conventional basic hydrolysis. e.g., using aqueous sodium hydroxide or the like, afford the corresponding 17(xand l7 fl-(carboxy aliphatic hydrocar-bonoxy)-A -estratrienes (IV; X=COOH), e.g., 17ccand 17B-(2'carboxyethoxy)-3-methoxy-A estratriene being obtained by hydrolyzing 17aand 17 3-(2- cyanoethoxy)S-methoxy-Ab -estratriene.

Treatment of the 17-(carboxy aliphatic hydrocarbonoxy) compounds with a lower alkyl magnesium halide, such as methyl magnesium bromide and the like, under conventional conditions, produces the' corresponding 17ozand 17;8-(n-hydroxy-n-alkyl aliphatic hydrocarbonoxy)-A -estratrienes (III; R =H), n' being the carbon atom of the aliphatic hydrocarbonoxy group to which the hydroxy and alkyl groups are attached, e.g., 17w and 17fl-(3-hydroxy-3'-methyl-butoxy)-3-methoxy- A -estratriene being the products resulting from the reaction of 17aand '17,3-(2-carboxyethoxy)-3-methoxy- A -estratriene with methyl magnesium bromide. Dehydration of these l7-(n'-hydroxy-n'-alkyl aliphatic hydrocarbonoxy) intermediates, for example by treatment with mesyl chloride in dimethyl formamide-pyridine at about C. for about 3 hours, results in the corresponding 17w and 17B-(unsaturated aliphatic hydrocarbonoxy)-A -estratrienes (IV; X=H, R is unsaturated), e.g., 17aand 1713-(3-hydroxy-3-methylbutoxy)-3-methoxy-A estratriene yielding, on dehydration, 17ocand 1719-(3'-methyl-but-2-enyloxy-3- 3. niethoxy-n -estratriene. Catalytic hydrogenation of these 17 (unsaturated aliphatic hydrocarbonoxy)- A -esteratrienes, e.g., at atmospheric pressure using a 5% palladium-on-charcoal catalyst, results in the corresponding 17aand 17,8-(saturated aliphatic hydrocar- -bonoxy)-A -estratrienes (IV; X=H, R is saturated), e.g., 17:- and 17p-(3'methyl-but-2'-enyloxy-3- methoxy A -estratriene, upon catalytically hydrogenation, yield 17aand 17B- (isoamyloxy)-3-methoxy- A -estratriene.

Oxidation of a 17-(hydroxy aliphatic hydrocarbonoxy)- A -estratriene (III; R :H), e.g., 1701- or 17542- hydroxyethoxy) 3 methoxy-A -estratriene, preferably using chorrnium trioxide in pyridine, gives the corresponding l7-(oxo-aliphatic hydrocarbonoxy)-A estratriene (IV; X aldehydic oxygen), e.g., l7otr 17(3- (2-oxoethoxy)-3-methoxy-A -estratriene. These 17- (oxo-aliphatic hydrocarbonoxy) derivatives, when treated with a lower alkyl, lower alkenyl or lower alkinyl magnesium halide, such as methyl magnesium bromide, vinyl magnesium bromide, ethinyl magnesium bromide, and the like, using conventional conditions, yield the corresponding 17w and 17p-[n-hydroxy-n-lower (alkyl, alkenyl or alkinyl) aliphatic hydrocarbonoxy] A -estratrienes (III; X=H, R is saturated or unsaturated), 11' again being the carbon atom of the aliphatic hydrocarbonoxy group to which the hydroxy and lower alkyl, alkenyl or alkinyl groups are attached, e.g., 17aand 17fl-(2'-hydroxypropoxy)-3-rnethoxy-A -estratriene, 17aand 17,8- (2 hydroxy but 3' enyloxy)-3-rnethoxy-A estratriene and 17uand 17,8-(2'-hydroxybut-3-inyloxy)- 3-methoxy-A -estratriene resulting from the reaction of 17aand l7fi-(2'-oxoethoxy)-3-methoxy-A estratriene with methyl, vinyl and ethinyl magnesium bromide, respectively.

The 3-ethers of the novel 17-(aliphatic hydrocarbonoxy)- and 17-(substituted aliphatic hydrocarbonoxy)- A -estratrienes (III and IV; R l-I, acyl), and preferably those wherein R represents hydrogen, Z represents a saturated linkage at the 6,7-position and X represents hydrogen or N,N-dialkylamino, are readily converted to the corresponding 17-(aliphatic hydrocarbonoxy)- and l7-(substituted aliphatic hydrocarbonoxy) A -estren-3- ones. This can be accomplished, for example, by first reacting the starting A -estratriene, e.g., 17ocor 175 (isoamyloxy)-3-methoxy-A -estratriene, with an alkali metal, e.g., lithium, in liquid ammonia, then diluting the reaction mixture with ethanol to give the corresponding A estradiene intermediate, e.g., 170:- or 17/3- (isoamyloxy)-3-methoxy-A -estradiene, and finally hydroylzing this A -intermediate with a mineral acid such as hydrochloric acid and the like to produce the corresponding 17-(aliphatic hydrocarbonoxy)- and 17-(substituted aliphatic hydrocarbonoxy)-A -estren-3- ones (V and VI), e.g., 17ocor 17fl-(isoarnyloxy)-A estren-3-one.

The novel 17-(halo aliphatic hydrocarbonoxy)-A estren-3-ones of the present invention, e.g., the 17-(2' haloethoxy)-A -estren-3-ones (VI; Y=halo), are preferably obtained by first tosylating the corresponding 17- (hydroxy aliphatic. hydrocarbonoxy)-A estren-3-ones and then reacting the tosylated intermediates with an alkali metal halide in the manner described hereinabove.

The compounds of the present invention having a primary, a secondary or a phenolic hydroxyl group, for example, the compounds represented by the Formula I above wherein R represents hydrogen or the compounds of Formula III above wherein OR represents a primary.

or secondary hydroxyl group, are preferably acylated by reaction with a suitable acid chloride or anhydride in pyridine in the manner well known in the art. Similarly, the compounds of the present invention having a tertiary hydroxyl group, for example, the compounds represented by Formula III above wherein 0R represents a tertiary hydroxyl group, are preferably esterified by reaction with a suitable acid anhydried in pyridine, in the presence of an acid catalyst such as p-toluenesulfonic acid and the like, in the manner well known in the art.

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

PREPARATION 1 To a suspension of 25 g. of l-methyl estrone in 25 cc. of acetone there was added a solution of 70 g. of potassium hydroxide in 37.5 cc. of water and the stirred mixture was treated dropwise with 40 cc. of methyl sulfate. The reaction mixture was then stirred for 45 minutes further, poured into dilute hydrochloric acid solution and the formed precipitate collected by filtration. The collected solid was washed with water to neutral, and dried under reduced pressure. Chromatography of the dry residue on 300 g. of alumina, followed by crystallization of the solid fractions eluted, from a mixture of chloroform-methanol, furnished the methyl ether of 1- methyl estrone.

Following the same procedure there were treated:

N -dehydroestrone and l-methyl-A -dehydroestrone,

thus yielding respectively:

The methyl-ether of A -dehydroestrone and The methyl-ether of 1-methyl-A -dehydroestrone.

Example I A mixture of 1 g. of estrone methyl ether, 25 cc. of dry benzene, 5 g. of ethyleneglycol, 50 mg. of p-toluenesultonic acid monohydrate, was refluxed for 16 hours using a water separator. It was then washed with a sodium bicarbonate solution, water and subsequently dried and evaporated to dryness. Recrystallization from acetonehexane yielded l7-(cycloethylenedioxy) 3 methoxy-A -estratriene (Compound No. 1).

Example II A solution of 1 g. of Compound No. 1 in 50 cc. of tetrahydrofuran was added over a 30 minutes period to a. stirred suspension of Y1 g. of lithium aluminum hydride and 6 g. of aluminum trichloride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly Washed with hot ethyl acetate; the combined. organic solutions upon evaporation yielded a crude material, which after chromatography and crystallization of the solid fractions from acetone-hexane atforded two products, predominantly 17B (2' hydroxy ethoxy)-3-methoxy-A l v-estratriene (Cpd. No. 2) and 17a-(2'-hydroxy ethoxy)-3- methoxy-A -estratriene (Cpd. No. 3) in smaller amount.

Example III A mixture of 1 g. of Compound No. 2, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 17p- (2-acetoxyethoxy) 3 methoxy-A -estratriene (Cpd. No. 4).

Example IV The Compound No. 2 was treated according to Example III except that acetic anhydride was substituted by caproic anhydride and cyclopentylpropionic anhydride, thus yielding respectively: 1713 (2' caproxyethoxy) 3 methoxy-A -estratriene (Cpd. No. 5) and 17,8-(2"- cyclopentylpropionoxy ethoxy) 3 methoxy A estratriene (Cpd. No. 6).

7 Example V A solution of l g. of Compound No. 2 in cc. of pyridine was treated with 0.5 g. of tosyl chloride and kept at room temperature for 24 hours, it was then diluted with water and the precipitate separated by filtration, thus giving 17B (2' tosyloxyethoxy) 3 methoxy A estratriene (Cpd. No. 7).

Example VI A suspension of g. of potassium fluoride in 50 cc. of dimethyl formamide was heated to boiling and then a solution of 2 got Compound No. 7 in 10 cc. of dimethyl formamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The formed precipitate was filtered off and crystallized to give 17,3 (2 fluoroethoxy) 3-methoxy-A -estratriene (Cpd. No. 8).

Example VII The Compound No. 7 was treated according to Example VI, except that potassium chloride was used instead of potassium fluoride, thus yielding l7fl-(2-chloroethoxy) 3-methoxy-A -estratriene (Cpd. No. 9).

Example VIII A solution of 1 g. of CompoundNo. 7 in 50 cc. of dioxane was treated with a constant stream of dimethylamine during 48 hours. Thereafter, the solution was boiled under reflux for 30 minutes and poured into water, thus aflording a precipitate which was filtered otT, dried and recrystallized from methanol-benzene, thus furnishing 17B-(2' [N,N dimethylamino]-ethoxy)-3-methoxy- A -estratriene (Cpd. No. 10).

Example IX A mixture of 1 g. of Compound No. 7, 1 g. of potassium cyanide and 50 cc. of acetonitrile was kept at 100 C. for 3 hours. The mixture was then poured into water, and the formed precipitate filtered off, dried and crystallized from acetone-hexane, thus yielding 17fl-(2'-cyanoethoxy)-3-methoxy-A -estratriene (Cpd. No. 11).

Example X A mixture of 1 g. of Compound No. 11, and 50 cc. of a 5% solution of sodium hydroxide in methanol, was refluxed during 4. hours, then cooled, acidified with hydrochloric acid and diluted with water. The formed precipitate was collected by filtration and recrystallized from acetone-hexane, thus yielding 17,8-(2'-carboxyethoxy)-3- methoxy-A -estratriene (Cpd. No. 12).

Example XI Example XII l g. of Compound No. 13 was dissolved with slow heating in 12.5 cc. of dimethyl-tormamide, the mixture was cooled, 0.42 g. of mesyl chloride and 0.5 cc. of pyridine were added and the solution was kept at 80 C. for 3 hours. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 8. 17B (3' methyl-but-2'-enyloxy)-3-methoxy-A -estratriene (Cpd. No. 14).

Example XIII A suspension of 0.5 g. of 5% palladium on carbon catalyst in cc. of methanol was hydrogenated for 30 minutes. A solution of 2 g. of Compound No. 14 in 200 cc. of methanol was added to the catalyst and stirred under a hydrogen atmosphere until the uptake of hydrogen ceased. After removal of the catalyst by filtration the solution was evaporated and the crude residue was purified by crystallization from methylene-chloride-hexane, thus giving 17B-(isoarnyloxy)-3-methoxy-A -estratriene (Cpd. No. 15).

Example XIV A cold solution of 6 g. of Compound No. 15 in 750 cc. of anhydrous ether was added to 900 cc. of liquid ammonia and then 7.8 g. of lithium wire over 10 minutes, with constant stirring. The mixture was stirred for 20 minutes more, 160 cc. of absolute ethanol were then cautiously added and the ammonia was allowed to evaporate. Water was added to the residue, the ether distilled off and .the resulting 17/3-(isoamyloxy)-3-methoxy-A -estradiene (Cpd. No. 16) collected, washed with water and dried.

A mixture containing the latter compound, 220 cc. of methanol and 132 cc. of 3 N hydrochloric acid was heated at C. for 18 minutes. The solution was cooled, poured into iced water and the resulting precipitate was collected, washed with water and dried. Crystallization from acetone-hexane yielded 17fl-(isoamyloxy)-A -estren 3 one (Cpd. No. 17).

Example XV The Compounds Nos. 2, 3, 10 and 13, were treated according to Example XIV, thus affording respectively the following final products:

Cpd. No.2

1817{i-(2'-hydroxyethoxy)-A -estren-3-one 1917a-(T-hYGIOXYethOXY)-A -eStl6I1-3-On6 20--17;8- (2'-[N,N-dimethylamino] -ethoxy) -A estren-3-one 21-17fl-(3'-hydroxy-3'-methyl-butoxy) A estren- 3-one Example X VI The Compound No. 18 was treated successively according to Examples V and VI, thus yielding respectively: 17p-(2'-tosyloxyethoxy)-A -estren-3-one (Cpd. No. 22) and 17/8-(2-fiuoroethoxy)-A -estren-3-one (Cpd, No. 23).

Example XVII The Compound No. 22 was treated according to Example VII, thus furnishing 17fi-(2'-chloroethoxy)-A estren-3-one (Cpd. No. 24).

Example XVIII The Compound No. 18 was treated in accordance with Examples Nos. III and IV, thus yielding respectively:

Cpd. No.:

25-17B-(2'-acetoxyethoxy)-A -estren-3-one 26-17/3-(2'-caproxyethoxy) -A -estren-3-one 2717fl-(2'-cyclopentylpropionoxyethoxy) -A -estren-3-one Example XIX The Compound No. 3 was treated according to Examples III, IV and V, to produce respectively:

Cpd. No.:

28-17a- (2-acetoxyethoxyl) -3 -methoxy-A estratriene Example XX The Compound No. 31 was treated according to Examples VI, VII, VIII and IX, thus furnishing respectively:

Cpd. No.:

3217a-(2-fluorodthoxy)-3-methoxy-A estratriene 3 317a-(2-chloroeth0xy) -3-methoxy-A estratriene 34-17a-(2'-[N,N-dimethylarnino] -ethoxy) -3- methoxy-A -estratriene -17a-(2-cyanoethoxy) -3-methoxy-A estratriene Example XXI The Compound No. 35 was treated consecutively in accordance with Examples X, XI, XII and XIII, thus affording respectively:

Cpd. No.:

3 617a-(2-carboxyethoxy) 3-methoxy-A estratriene 37-17a-(3-hydroxy-3-methyl-but-oxy)-3-methoxy-A -estratriene 3 8-1 '/'a (3 -methyl-but-2-enyloxy) -3-methoxy- A -estratriene 39-17a-(isoamyl0xy)-3-methoxyA -estratriene Example XXII The Compounds Nos. 34, 37 and 39 were treated by the procedure described in Example XIV, thus aifording, respectively, final products:

Cpd. No.:

4017u (2'- [N,N-dimethylamino] -ethoxy) -A estren-3-one 41-17a-(3-hydroxy-3'-methylbutoxy) A estren- 3-one 4217a-(isoamyloxy)-A -estren-3-one Example XXIII The Compound No. 19 was treated, successively, according to Examples V and VI, thus yielding respectively: 17a-(2'-tosyloxyethoxy)-A -estren-3-one (Cpd. No. 43), and 17a-(2'-fluoroethoxy)A -estren-3-one (Cpd. No. 44).

Example XXIV The Com-pound No. 43 was treated according to Example VII, thus furnishing 17a-(2'-chloroethoxy-A -estren-3-one (Cpd. No. 45).

Example XXVI The starting compounds set forth under A, were treated 19 according to Example I, thus affording the corresponding products listed hereinafter under B:

A Cpd.

Estrone 17-eyclocthylenedioxy-8- hydroxy-A -estratriene. 17-oye10ethy1enedioxy-3- benzyloxy-A -estratriene. 17-eyc1oethy1enedioxy3-nbutoxy-A estratriene. 17-cycloethy1enedi0xy-3-ndecyloxy-A M10) -estratriene. 17-cyeloethy1enedioxy-3- cyc1openty10 y.Al .a .500) estratriene. 17-cyc1oethy1enedi0xy-3- isoamyloxy-A 0 estratriene. 17-cyoloethylenedioxy-3- hydroxy-l-metnyl- A -estratriene. 17-cye1oethylenedioxy-3- methoxy-l-methyl- A J -estratriene. 17-eye10ethylenedioxy-3- h d 1,a,s(10) .aestratetraene. 17-cycloethy1enedioxy-3- t 1,s,5(10) .0. estratetraene. 17-cycloetl1ylenedioxy-3 hydroxy-Lmethyl-A ,3 M10) estratetraene. 17-cycl0ethylenedioxy-3- methoxy-l-methyl-A M00) Benzyl ether of estrone n-Buty1 ether of estrone n-Decyl ether 01' estrone.

Cyclopentyl ether of estrone Isoamyl ether of esti'one l-VIethyl estrone Methyl ether of 1-rnethyl estrone.

A dehydroestmne Methyl ether of M-dehydro estrone:

1-methyl-A -dehydroestrone Methyl ether of l-methyl-A dehydmestrone.

estratetraene.

Example XX VII The Compounds Nos. 49 to inclusive, were treated according to Example II, thus yielding, predominantly, the respective products listed hereinafter under A, and in smaller amount, those listed under B.

Cpd. A Cpd. B

No. No.

61 17B-(2-hydroxyeth0xy)-3- 73 17a-(2-hydroxy ethoxy)- h d 1.3,5(1o) 1.s,s 1o) estratriene. estratriene.

62 17B-(2-hydroxyethoxy)-3- 74 17a-(2-hydroxy eth0xy)- benzyloxy-A fl 3-benzy1oxy-A estratriene. estratriene.

63 17B-(2-hydroxyethoxy)-3- 75 17a-(2-hydroxy ethoxy) n-butoxy-A tl-rl'butoxy-A M10) estratriene. estratriene.

64 17B-(2-hydroxyethoxy)-3- 76 17a-(2-hydroxy ethoxy)- n-deoyloxy-A M10) 3-n-decy1oxy-A estratriene. estratriene.

1713-(2-hydroxyethoxy)3- 77 17a-(2hydroxy ethoxy)- oyclopentyloxy- 3-eyclopentyloxy- A -estratriene. A estratr1ene.

66 17B-(2-hydroxyethoxy)-3- 78 1711-(2 -hydroxy eth0xy)- isoamyloxy-A 3-isoarr1yloxy-A estratriene. estratrlene.

68 17B-(2-hydroxyethoxy)-3- 80 17a-(2-hydroxy ethoxy)- methoxy-l-methyl- 3-methoxy-1-methy1- A ,5(l0)-estratrie11e. A -estratr1ene.

69. i 17B-(2-hydroxyethoxy)-3- 81 17a-(2-hydroxy ethoxy)- hydr xy.A1,3 .500) .5. 1.a.5(1o) ,a. estratetraene. estratetraene.

l7fl(2-hydroxyethoxy)-3- 82 17a-(2-hydr0xy etl1oxy)- methoxy-A 3-500) 3-methoxy-A estratetraene. estratetraene.

71, 17 3-(2 -hydroxyethoxy) -3- 83 1701- (2 -hydroxy ethoxy)- hydroxy-l-methyl- 3-hydroxy-1-1nethyl- A M10) --estratet-raene. A 315m) -estratetraene.

methoxy-l-me y A M0 -estratetraene.

S-methoxy-l-methyl- AIMUO) -estratetraene.

Example XXVIII according to Example III, thus yielding respectively:

Cpd. No.:

estratriene 86-l7B-(2'-acetoxy ethoxy)3-benzyloxy M estratriene 8717,8-(2'-acetoxy ethoxy)-3-butoxy-A estratriene estratriene Upon treatment of Compounds Nos. 61 to 72, inclusive, by the procedures of Example IV, there were obtained the corresponding compounds having, respectively, caproxy and cyclopentylpropionoxy groups instead of acetoxy groups.

Example XXIX The Compounds Nos. 61 to 72, inclusive, were treatedaccording to Example V, thus affording the corresponding l7fi-(2-tosyloxy ethoxy) derivatives, which in turn were treated in accordance with Example V'I, giving respectively:

10117/8-(2-fluoro ethoxy)-3-cyclopenty1oxy- A -estratriene 102-17/3-(2-fiuoro ethoxy)-3-isoamyloxy-A estratriene 10317/3-(2-fiuoro ethoxy)-3-hydroxy-1-methyl- A -estratriene 104--17B-(2'-fluoro ethoxy)-3-methoxy-1-methyl- A -estratrine 10717B-(2'-fluoro ethoxy)-3-hydroxy-1-methyl- A -estratetraene 10817B- (2-fiuoro ethoxy -3 -methoxy-1-methyl- A -estratetraene By treatment of 17fl-(2'-tosyloxy-ethoxy) compounds mentioned hereinbefore by the procedure of Example VII, there were produced the corresponding 17;.8-(2'- chloro ethoxy) compounds.

Example XXX When treating the 17,8-(2tosyloxy ethoxy) compounds of Example XXIX, in accordance with Examples VIII and IX, there were produced, respectively, the corresponding 17B-(2'-[N,N-dimethylamino]ethoxy) and 17B- (2-cyano ethoxy) derivatives.

The latter derivatives, in turn, were treated successively, by the procedures described in Examples X, XI, XII, and XIII, thus yielding, respectively, the corresponding 17B-(2carboxy ethoxy), 17B-(3'-hydroxy-3-methyl-butoxy), 1718-(3'-methyl-but-2-enyloxy) and 17fl-(isoamyloxy) compounds.

Example XXXI The reactions set forth in Examples XXVIII, XXIX, and XXX for the 17,8-c-ompounds, were applied to the 170t-COl'llpOlJI1dS described in Example XXVII, thus yielding the corresponding 17a-isomers of the products of said examples.

Examples XXXII Estrone methyl ether was treated according to Example I, except'that ethyleneglycol was substituted by hexamethylene glycol (1,6-hexanediol) and by 2,3-hexane diol, thus yielding respectively 17-(cyclohexamethylene dioxy)- B-methoxy-A -estratriene (Cpd. No. 109), and 17- (hexane-2',3-dioxy)-3-methoxy-A -estratriene (Cpd. No. 110). These compounds when treated by the procedure described in Example II, yielded, respectively and predominantly 17,8 (6 hydroxyhexyloxy)-3-methoxy- A -estratriene (Cpd. No. 111) and 175-(3'-hydroxyhexyl-2-oxy)-3-methoxy-A -estratriene (Cpd. No. 112) and in smaller amount the corresponding 17a-isomers thereof.

Example XXXIII The starting compounds of Example XXVI were treated in accordance with Example XXXII, thus being produced the corresponding 17-(cyclohexamethylenedioxy) and 17-(hexane-2',3-dioxy) derivatives and therefrom, respectively and predominantly, the corresponding 17fl-(6'- hydroxyhexyloxy)- and 17fi-(3-hydroxy hexyl-2-oxy) compounds and in smaller amount the corresponding 17aisomers thereof.

Example XXXIV A solution of 6 g. of compound No. 2 in 120 cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane atforded 1713- (2-oxo ethoxy)-3-methoxy-A -estratriene (Cpd. No. 113).

Upon treatment of the latter compound by the procedure described in Example XI, there was produced 175- (2 hydroxy propoxy)-3-methoxy-A -estratriene (Cpd. No. 114).

p The CompoundsNos. 61 to 72, inclusive were treated by the same procedures thus yielding firstly the corresponding 17 8-(2-oxoethoxy)derivatives and secondly the following respective compounds.

Cpd. No.:

11517 8-(2'-hydroxy propoxy)-3-hydroxy-A estratriene l16-17fl- (2' -hydroxy propoxy -3 -benzyl0xy- A -estratriene 1 1717}3-(2-hydroxy propoxy) -3-n-butoxy- A -estratriene 11817fl-(2'-hydroxy propoxy)-3-n-decyloxy- A -estratriene 1 19-17B-(2-hydroxy propoxy)-3-cyclopentyloxy- A -estratriene 120'17fi-(2'-hydroxy propoxy)-B-isoamyloxy- A -estratriene 12 1-1 713- (2'-hydroxy propoxy) -3-hydroxy-1- methyl-A 3 -estratriene 122-17,8-(2-hydroxy propoxy)-3-rnethoxy-1- methyl-A -estratriene 12317,B-(2-hydroxy propoxy)-B-hydroxy- A -estratetraene 124-17/3-(2'-hydroxy propoxy)-3-methoxy- A -estratetraene 125-17fl-(2-hydroxy propoxy)-3-hydroxy-1- methyl-A -estratetraene 12617;8-(2'-hydroxy propoxy)-3-methoxy-lmethyl-A -estratetraene Example XXX V '75 magnesium bromide, thus yielding respectively: 17,9-(2'- 13 hydroxy but 3'-enyloxy)-3 -methoxy A -estratriene (Cpd. No. 127) and 17B-(2'-hydroxy-but-3'-inyloxy)-3- methoxy-A -estratriene (Cpd. No. 128).

The rest of the 17,8-(2'-oxoethoxy) derivatives obtained in accordance with Example XXXIV were treated by the same procedures, thus yielding respectively, the corresponding 17B-(2-hydroxy-2'-vinyl-ethoxy) and 17fl-(2- hydroxy-2-ethinyl-ethoxy) compounds.

Example XXXVI The Compounds Nos. 111,112, 114, 127 and 128 were treated according to Example III, thus yielding respectively:

Cpd. No.

1291 78- 6'-acetoxy-hexyloxy -3 -methoxy- A -estratriene 130-1 7;?- 3 -acetoxy-hexyl-2'-oxy -3-methoxy- A1135 -estratriene 131-17,8-(2-acetoxy-propoxy)-3 -methoxy- A -estratriene 13217,8- (2-acetoxy-but-3-enyloxy) A -estratriene 13 317fi- 2-acetoxy-but-3 -iny1oxy -3-methoxy- A13,5 -estratriene Upon treatment of the above starting compounds in accordance with Example IV, there were obtained the corresponding caproxy and cyclopentylpropionoxy derivatives.

Example XXX VII The Compounds Nos. 14, 111, 112, 114, and 127 were treated according to Example XIV, thus yielding respectively:

Cpd. No.

13417/3- 3 -methyl-but-2'-enyloxy A -estren-3-one 13517B-(6'-hydroxyhexyloxy)-A -estren-3-one 13 617fl- 3 '-hydroxyhexyl-2'-oxy -A -estren-3-one 13717B- (2-hydroxypropoxy) -A estren-3-one 13 817,8- (2-hydroxy-but-3'-enyloxy -A -estren- 3 -one Example XXXVIII Y Upon treatment of Compound No. 128 by the procedure of Example XIV, there were produced: 17/3-(2- hydroxy-but-3'-enyloxy)-A -estren-3-one (Cpd. No. 138) and 17B (2' hydroxy but 3.-inyloxy)-A -estren-3-one (Cpd. No. 139).

Example XXXIX The Compounds Nos. 134 to 139, inclusive, were treated according to Examples Nos. III and IV, thus alfording the corresponding acetoxy, caproxy and cyclopentylpropionoxy derivatives.

Example XL To a solution of 5 g. of Compound No. 13 in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from etherhexane produced 17,8-(3-acetoxy-3-methyl-butoxy)-3- methoxy-A -estratricne (Cpd. No. 140). By the same procedure, Compound No. 21 was converted into 175-6- acetoxy 3' methyl-butoxy)-A -estren-3-one (Cpd. No. 141).

Example XL] The Compounds Nos. 114 to 128, inclusive were treated according to Example V, thus yielding the corresponding tosyloxy derivatives, which upon treatment in accordance with Examples VI, VII, VIII, and IX afforded, respectively the corresponding (fluoro, chloro,

RO-OV wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive, OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms, and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7-position, and X is halogen. H

; 10. A compound represented by'the general formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl and an acyloxy group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7-position, and X is an N,N-dialkylarnino group.

11. A compound represented by the general formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is selected from the group consisting of hydroxyl, an acyloxy group containing less than 12 carbon atoms, and an ether group containing from 1 to 12 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of a saturated linkage and a double bond at the 6,7-position, and X is a carboxyl group.

15 12. A compound represented by the general O-RX* ,gn od,

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive; OR is formula selected from the group consisting of hydroxyl, an acyloxygroup containing less than 12 carbon atoms, and an ether group containing from 1 tov 12 carbon atoms, inclusive; R is selected fromv the group consisting of hydrogen and methyl; Z is selected from the group consisting of a satu-' rated linkage and a double bond at the 6,7-position, and X is an aldehydic oxygen.

14. A compound represented by the general formula:

wherein R representsan alihpatic hydrocarbon residue.

containing from l to 10 carbon atoms, inclusive, and Y is halogen.

15: A compound represented by the general formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 10 carbon atoms, inclusive, and Y is an N,N-dilalkylamino group.

16. A compound having the formula wherein X is lower alkylene and R is lower alkyl.

17. A compound having the formula wherein X is lower alkylene,

References Cited UNITED STATES PATENTS 4/1961 Van Dorp et al. 260397.45

FOREIGN PATENTS 803,440 10/ 1958 Great Britain. 804,789 11/1958 Great Britain.

ELBERT L. ROBERTS, Primary Examiner.

LEWIS GOT'ITS, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,374,251 March 19, 1968 Alexander D. Cross It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, the upper right-hand portion of formula "A" readlng (541410 should read (gm-0R Column 3, the upper right-hand portion of formula "VI" reading g-R-X should read (il-R-Y Column 11, ldne 44, "-estratrine" should read estratriene Column 14, 11ne ll, "-estratri-" should read -estratriene Signed and sealed this 12th day of August 1969.

(SEAL) Attest:

EDWARD MJLETCHERJR. WILLIAM E. SCHUYLER,JR. Attestlng offlcer Commissioner of Patents 

1. 17-(2''-FLUOROETHOXY)-3-MTHOXY-$1,3,5(10)-ESTRATRIENE. 